tbuckley/cabot-search huggingface dataset:
Vector Aided Microenvironment programming (VAMP): reprogramming the TME with MVA virus expressing IL-12 for effective antitumor activity
Authors: Laura Seclì, Luigia Infante, Linda Nocchi, Maria De Lucia, Gabriella Cotugno, Guido Leoni, Elisa Micarelli, Irene Garzia, Lidia Avalle, Giulia Sdruscia, Fulvia Troise, Simona Allocca, Giuseppina Romano, Elisa Scarselli, Anna Morena D'Alise
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Tumor microenvironment (TME) represents a critical hurdle in cancer immunotherapy, given its ability to suppress antitumor immunity. Several efforts are made to overcome this hostile TME with the development of new therapeutic strategies modifying TME to boost antitumor immunity. Among these, cytokine-based approaches have been pursued for their known immunomodulatory effects on different cell populations within the TME. IL-12 is a potent pro-inflammatory cytokine that demonstrates striking immune activation and tumor control but causes severe adverse effects when systemically administered. Thus, local administration is considered a potential strategy to achieve high cytokine concentrations at the tumor site while sparing systemic adverse effects. Methods Modified Vaccinia Ankara (MVA) vector is a potent inducer of pro-inflammatory response. Here, we cloned IL-12 into the genome of MVA for intratumoral immunotherapy, combining the immunomodulatory properties of both the vector and the cargo. The antitumor activity of MVA-IL-12 and its effect on TME reprogramming were investigated in preclinical tumor models. RNA sequencing (RNA-Seq) analysis was performed to assess changes in the TME in treated and distal tumors and the effect on the intratumoral T-cell receptor repertoire. Results Intratumoral injection of MVA-IL-12 resulted in strong antitumor activity with the complete remission of established tumors in multiple murine models, including those resistant to checkpoint inhibitors. The therapeutic activity of MVA-IL-12 was associated with very low levels of circulating cytokine. Effective TME reprogramming was demonstrated on treatment, with the reduction of immunosuppressive M2 macrophages while increasing pro-inflammatory M1, and recruitment of dendritic cells. TME switch from immunosuppressive into immunostimulatory environment allowed for CD8 T cells priming and expansion leading to tumor attack. Conclusions Intratumoral administration of MVA-IL-12 turns immunologically ‘cold’ tumors ‘hot’ and overcomes resistance to programmed cell death protein-1 blockade.
When I use a word . . . Medical definitions: Pharmacovigilant surveillance
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

Having previously offered a long extensional definition of “pharmacovigilance,” I now offer a shorter, intensional definition: “A scientific activity related to the benefits and harms of any intended therapeutic intervention, primarily involving accurate identification and quantification, mechanistic analysis, continued surveillance, communication, and prevention of its adverse effects, adverse reactions to it, and adverse interactions with other interventions.” A major aspect of pharmacovigilance is continued surveillance for beneficial effects and particularly adverse events, effects, and reactions. Colleagues and I have proposed the following definition of “surveillance”: “a form of non-interventional public health research, consisting of a set of processes for the continued systematic collection, compilation, interrogation, analysis, and interpretation of data on benefits and harms (including relevant spontaneous reports, electronic medical records, and experimental data).” We have also proposed that instead of using qualifiers of surveillance, such as “active” and “passive,” a single definition of “surveillance” is sufficient, and that in any description of a particular method of surveillance the precise way in which the method is used should be detailed.
Reply to letter to the editor “Bureaucracy or Streamlining the Rules in “Good Clinical Practice (GCP)” - Has Equipoise Occurred?” by H. K. Kotikonda, V. G. Jonnalagadda and S. R. Venna
Authors: J.L. Perez-Gracia, N. Penel, E. Calvo, H.T. Arkenau, T. Amaral, V. Grünwald, M.F. Sanmamed
Journal: Annals of Oncology (2023)
Gelatin Methacryloyl Hydrogel, from Standardization, Performance, to Biomedical Application
Authors: Jing He, Yuan Sun, Qing Gao, Chanfan He, Ke Yao, Tongyao Wang, Mingjun Xie, Kang Yu, Jing Nie, Yuewei Chen, Yong He
Journal: Advanced Healthcare Materials (2023)

Gelatin methacryloyl (GelMA), a photocurable hydrogel, is widely used in 3D culture, particularly in 3D bioprinting, due to its high biocompatibility, tunable physicochemical properties, and excellent formability. However, as the properties and performances of GelMA vary under different synthetic conditions, there is a lack of standardization, leading to conflicting results. In this study, a uniform standard is established to understand and enhance GelMA applications. First, the basic concept of GelMA and the density of the molecular network (DMN) are defined. Second, two properties, degrees of substitution and ratio of solid content, as the main measurable parameters determining the DMN are used. Third, the mechanisms and relationships between DMN and its performance in various applications in terms of porosity, viscosity, formability, mechanical strength, swelling, biodegradation, and cytocompatibility are theoretically explained. The main questions that are answered: what does performance mean, why is it important, how to optimize the basic parameters to improve the performance, and how to characterize it reasonably and accurately? Finally, it is hoped that this knowledge will eliminate the need for researchers to conduct tedious and repetitive pre-experiments, enable easy communication for achievements between groups under the same standard, and fully explore the potential of the GelMA hydrogel.
Treatment of US Children With Attention-Deficit/Hyperactivity Disorder in the Adolescent Brain Cognitive Development Study
Authors: Mark Olfson, Melanie M. Wall, Shuai Wang, Gonzalo Laje, Carlos Blanco
Journal: JAMA Network Open (2023)

Importance Characterizing the extent and pattern of unmet needs for treatment of children with attention-deficit/hyperactivity disorder (ADHD) could help target efforts to improve access to ADHD medications and outpatient mental health care. Objective To describe current ADHD medication use and lifetime outpatient mental health care among a large national sample of children with ADHD. Design, Setting, and Participants This study uses cross-sectional survey data from the first wave of the Adolescent Brain and Cognitive Development Study (n = 11 723), conducted from June 1, 2016, to October 15, 2018, among 1206 school children aged 9 and 10 years who met parent-reported Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for current ADHD. Statistical analysis was performed from March 23, 2022, to March 10, 2023. Main Outcomes and Measures Current ADHD medications including stimulants and nonstimulants, lifetime outpatient mental health care, or either treatment. Weighted results are reported. Results Among a sample of 11 723 children, 1206 had parent-reported ADHD (aged 9-10 years; 826 boys [68.2%]; 759 White, non-Hispanic children [62.2%]), 149 (12.9%) were currently receiving ADHD medications. Children receiving ADHD medications included a significantly higher percentage of boys (15.7% [121 of 826]) than girls (7.0% [28 of 108]), White children (14.8% [104 of 759]) than Black children (9.4% [22 of 206]), children of parents without a high school education (32.2% [9 of 36]) than of parents with a bachelor’s degree or higher (11.5% [84 of 715]), and children with the combined subtype of ADHD (17.0% [83 of 505]) than with the inattentive subtype (9.5% [49 of 523]). Approximately 26.2% of children (301 of 1206) with parent-reported ADHD had ever received outpatient mental health care. Children receiving outpatient mental health care included a significantly higher percentage of children whose parents had a high school education (36.2% [29 of 90]) or some college (31.0% [109 of 364]) than a bachelor’s degree or higher (21.3% [153 of 715]), children with family incomes of less than $25 000 (36.5% [66 of 176]) or $25 000 to $49 999 (27.7% [47 of 174]) than $75 000 or more (20.1% [125 of 599]), and children with the combined subtype of ADHD (33.6% [166 of 505]) than with the predominantly inattentive subtype (20.0% [101 of 523]) or the hyperactive-impulsive subtype (22.4% [34 of 178]) of ADHD. Conclusions and Relevance This cross-sectional study of children with parent-reported ADHD suggests that most were not receiving ADHD medications and had never received outpatient mental health care. Gaps in treatment, which were not directly associated with socioeconomic disadvantage, underscore the challenges of improving communication and access to outpatient mental health care for children with ADHD.
Comparing Physician and Artificial Intelligence Chatbot Responses to Patient Questions Posted to a Public Social Media Forum
Authors: John W. Ayers, Adam Poliak, Mark Dredze, Eric C. Leas, Zechariah Zhu, Jessica B. Kelley, Dennis J. Faix, Aaron M. Goodman, Christopher A. Longhurst, Michael Hogarth, Davey M. Smith
Journal: JAMA Internal Medicine (2023)

The rapid expansion of virtual health care has caused a surge in patient messages concomitant with more work and burnout among health care professionals. Artificial intelligence (AI) assistants could potentially aid in creating answers to patient questions by drafting responses that could be reviewed by clinicians.
Assessment of Surrogate End Point Trends in Clinical Trials to Approve Oncology Drugs From 2001 to 2020 in Japan
Authors: Hideki Maeda, Riko Shingai, Kentaro Takeda, Asuka Hara, Yuna Murai, Momoka Ofuchi
Journal: JAMA Network Open (2023)

Importance A surrogate end point (SEP) is an end point used in clinical trials as an alternative for measuring the true clinical benefit. The use of SEPs in trials shortens their duration. Objectives To investigate the use of SEPs in clinical trials to support the approval of anticancer drugs and to determine whether confirmatory studies that use overall survival (OS) as an end point are being conducted in Japan. Design, Setting, and Participants In this cross-sectional study, drug approvals and background information were obtained from publicly available information, such as the Pharmaceuticals and Medical Devices Agency website, for anticancer drugs approved in Japan from January 2001 to December 2020. Data analysis was performed from September 2021 to March 2022. Main Outcomes and Measures Characteristics of approved oncology drugs in Japan, end points for pivotal clinical trials, and outcomes of confirmatory trials using OS as an end point following drug approval. Results There were 299 anticancer drugs approved in Japan during the study period. Of these, 142 (47.5%) were molecular-targeted drugs, the most common of which targeted non–small cell lung cancer. There were 111 (37.1%) anticancer drugs with orphan designation. From 2001 to 2005, OS was used as an end point in 1 approval (3.6%); however, from 2006 to 2020, OS was used in 86 approvals (31.7%). Of the 212 anticancer drugs approved on the basis of SEPs, confirmatory studies with OS as the end point were conducted for only 37 approvals (17.5%); for the remaining 175 approvals, studies are under way for 35 approvals (16.5%), were waivered for 75 approvals (35.4%), and were not conducted for 65 approvals (30.7%). Furthermore, in 20 drug approvals (9.4%), the conducted confirmatory studies were not effective in determining the OS, but the drugs were approved following re-examination. Conclusions and Relevance The findings of this study suggest that starting from 2005, the use of OS as an end point has increased in studies supporting the approval of anticancer drugs in Japan. However, even after 2005, approximately two-thirds of these approvals were SEP based. Postmarketing surveillance studies of the true end points are necessary to validate the use of SEPs.
Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury
Authors: Tobias Sieckmann, Gunnar Schley, Neslihan Ögel, Simon Kelterborn, Felix J. Boivin, Michael Fähling, Muhammad I. Ashraf, Martin Reichel, Emilia Vigolo, Andrea Hartner, Falk-Bach Lichtenberger, Tilman Breiderhoff, Felix Knauf, Christian Rosenberger, Felix Aigner, Kai Schmidt-Ott, Holger Scholz, Karin M. Kirschner
Journal: Kidney International (2023)
Abortion Policy Positions of Federal Legislators Who Received Support From the American College of Obstetricians and Gynecologists, 2012-2022
Authors: Karisma Chhabria, Vineet Raman, Ghazal Aghagoli, Benjamin P. Brown
Journal: JAMA Network Open (2023)

This cross-sectional study analyzes the abortion policy positions of legislators financially supported by Ob-GynPAC, a political action committee funded by the American College of Obstetricians and Gynecologists (ACOG), between 2012 and 2022.
Comparative Effectiveness of 2 Interventions to Increase Breast, Cervical, and Colorectal Cancer Screening Among Women in the Rural US
Authors: Victoria L. Champion, Electra D. Paskett, Timothy E. Stump, Erika B. Biederman, Eric Vachon, Mira L. Katz, Susan M. Rawl, Ryan D. Baltic, Carla D. Kettler, Eric E. Seiber, Wendy Y. Xu, Patrick O. Monahan
Journal: JAMA Network Open (2023)

Women living in rural areas have lower rates of breast, cervical, and colorectal cancer screening compared with women living in urban settings.
How Chatbots and Large Language Model Artificial Intelligence Systems Will Reshape Modern Medicine
Authors: Ron Li, Andre Kumar, Jonathan H. Chen
Journal: JAMA Internal Medicine (2023)

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Oligometastases: Characterizing the Role of Epigenetic Regulation of Epithelial–Mesenchymal Transition
Authors: Rohan R. Katipally, Sean P. Pitroda, Ralph R. Weichselbaum, Samuel Hellman
Journal: Clinical Cancer Research (2023)

The "oligometastasis" hypothesis proposes that metastases exist as a spectrum and are not always disseminated. According to this theory, a subset of patients with metastatic disease could benefit from aggressive local therapies. However, the identification of patients most likely to exhibit an oligometastatic phenotype remains challenging. Recent literature focusing on basic and translational studies has identified novel epigenetic regulators of epithelial-mesenchymal transition (EMT) and the emergence of a spectrum of metastatic behavior. Herein, we review these scientific advances and suggest that the spectrum of metastatic virulence produced by these epigenetic mechanisms broadly contributes to the emergence of clinically evident "oligometastases." Epigenetic regulation of EMT programs can result in a spectrum of cell trajectories (e.g., quasi-mesenchymal and highly mesenchymal states) with differential propensity to develop metastases. We propose that quasi-mesenchymal cell states may be associated with a polymetastatic phenotype, whereas highly mesenchymal cell states may be associated with a more oligometastatic phenotype. The mechanisms governing epigenetic regulation of EMT and its array of intermediate states are multifaceted and may contribute to the development of the metastatic spectrum observed clinically. Within this context, translational studies that support the role of EMT and its epigenetic regulation are discussed. Continued translation of these mechanistic discoveries into novel biomarkers may help optimally select patients most likely to exhibit an oligometastatic phenotype and benefit from aggressive local therapies, such as surgery, radiotherapy, and other ablative procedures.
Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04)
Authors: Arathi Mohan, Kent A. Griffith, Fulei Wuchu, David B. Zhen, Chandan Kumar-Sinha, Oxana Crysler, David Hsiehchen, Thomas Enzler, Dominique Dippman, Valerie Gunchick, Abhinav Achreja, Olamide Animasahun, Srinadh Choppara, Minal Nenwani, Arul M. Chinnaiyan, Deepak Nagrath, Mark M. Zalupski, Vaibhav Sahai
Journal: Clinical Cancer Research (2023)

Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC).
Time to Introduce Nerve Density in Cancer Histopathologic Assessment
Authors: Hubert Hondermarck, Chen Chen Jiang
Journal: Clinical Cancer Research (2023)

Summary The density of nerves in the tumor microenvironment is increasingly reported to be associated with worse clinical outcome in various cancers. Therefore, it is time to consider the assessment of nerve density in clinical cancer pathology, and interestingly, the development of artificial intelligence may facilitate this clinical translation. See related article by Perez-Pacheco et al., p. 2501
Integrative dissection of gene regulatory elements at base resolution
Authors: Zeyu Chen, Nauman Javed, Molly Moore, Jingyi Wu, Gary Sun, Michael Vinyard, Alejandro Collins, Luca Pinello, Fadi J. Najm, Bradley E. Bernstein
Journal: Cell Genomics (2023)

Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. Here, we combine epigenetic perturbations, base editing, and deep learning to dissect regulatory sequences within the exemplar immune locus encoding CD69. We converge on a ∼170 base interval within a differentially accessible and acetylated enhancer critical for CD69 induction in stimulated Jurkat T cells. Individual C-to-T base edits within the interval markedly reduce element accessibility and acetylation, with corresponding reduction of CD69 expression. The most potent base edits may be explained by their effect on regulatory interactions between the transcriptional activators GATA3 and TAL1 and the repressor BHLHE40. Systematic analysis suggests that the interplay between GATA3 and BHLHE40 plays a general role in rapid T cell transcriptional responses. Our study provides a framework for parsing regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants.
Mice identify subgoal locations through an action-driven mapping process
Authors: Philip Shamash, Sebastian Lee, Andrew M. Saxe, Tiago Branco
Journal: Neuron (2023)

Mammals form mental maps of the environments by exploring their surroundings. Here, we investigate which elements of exploration are important for this process. We studied mouse escape behavior, in which mice are known to memorize subgoal locations-obstacle edges-to execute efficient escape routes to shelter. To test the role of exploratory actions, we developed closed-loop neural-stimulation protocols for interrupting various actions while mice explored. We found that blocking running movements directed at obstacle edges prevented subgoal learning; however, blocking several control movements had no effect. Reinforcement learning simulations and analysis of spatial data show that artificial agents can match these results if they have a region-level spatial representation and explore with object-directed movements. We conclude that mice employ an action-driven process for integrating subgoals into a hierarchical cognitive map. These findings broaden our understanding of the cognitive toolkit that mammals use to acquire spatial knowledge.
Clonal Hematopoiesis in Young Women Treated for Breast Cancer
Authors: Christopher J. Gibson, Geoffrey Fell, Tal Sella, Adam S. Sperling, Craig Snow, Shoshana M. Rosenberg, Greg Kirkner, Ashka Patel, Deborah Dillon, Alexander G. Bick, Donna Neuberg, Ann H. Partridge, Peter G. Miller
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping. Experimental Design: We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study. Results: We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non–breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM. Conclusions: Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.